The art of microencapsulation has been the object of considerable attention in recent years in view of the increased necessity to maintain a reactive substance in an inert stage until the time it is required to perform a given function. Microencapsulation provides a number of benefits, the most outstanding being the capability of microcapsules to protect sensitive substances against chemical and physical degradation, to allow separation of substances which are harmful upon contact with each other, to mask an original odor, color or taste of a substances, to control dispersibility of substances, and to prevent undesirable release of an encapsulated substance to the formulation that contains it.
Microcapsules are available usually in powder form and consist of spherical particles, which contain an encapsulated (entrapped) substance. The spherical particle usually consists of a polymeric shell and the encapsulated substance is located within the shell. The polymeric shell is frequently applied as a wall-forming material and serves as a membrane for the encapsulated substance. This membrane may be semi-permeable or degradable, and therefore it allows the microcapsule to be an efficient tool for controlled release applications.
Microencapsulation itself has various advantages. Microcapsules protect sensitive substances from degradation processes and provide means for controlled release of desired active substances. It also enables the conversion of liquids to powders and is used to isolate substances that are otherwise detrimental when in contact with each other.
Numerous techniques for microencapsulation are available depending on the nature of the encapsulated substance and on the type of polymer used. A widely used method for encapsulation of water insoluble substances such as some vitamins, drugs and oils within water insoluble polymers is the solvent removal method. Generally in such a process the desired polymer is dissolved in a suitable organic solvent. This action is followed by addition of the desired substance to be encapsulated. This substance is either dissolved or dispersed in the organic solvent. The resulting organic solution or dispersion is dispersed in an aqueous phase to obtain an oil-in-water emulsion where oily microparticles are dispersed in the aqueous phase. Upon complete removal of the solvent from the microparticles, the microcapsules are formed.
Several patents describe methods of removing the solvent. U.S. Pat. No. 4,384,975 describes the removal of the solvent by vacuum distillation. In GB 1,394,780 the removal of the solvent is done by evaporation. In U.S. Pat. No. 3,891,570, the removal of the polymer solvent is carried out by heating the aqueous dispersion or by reducing its pressure, In U.S. Pat. No. 3,737,337 the removal of the organic solvent is done by extraction with water, however it is limited to certain solvent systems.
Microencapsulation is suitable for a large variety of materials including drugs, vitamins and food supplements, since this process is easily adaptable by varying the solvents and/or the polymers. Some microencapsulation technologies may yield microcapsules having desirable size, spherical shape and smooth surface—properties important for controlled release, for chemical stability of the core material, and homogeneous delivery of stable active substances to the target area.
A basic prerequisite for this process is the use of a solvent that is able to efficiently dissolve the biologically active substance to be encapsulated as well as the wall-forming material. This solvent has to be only partially soluble in water, giving rise to emulgation of an organic phase in a continuous water phase. Chlorinated solvents such as dichloromethane and chloroform as well as glycols or their mixtures with other solvents have been widely used since they facilitate the microencapsulation process.
However, all the microencapsulation technologies based on solvent systems such as chlorinated solvents are not applicable and are quite inappropriate for food, cosmetics, pharmaceutical, dental and oral products, since they do not meet FDA and other regulations due to the presence of residual amounts of chlorinated solvents in the microcapsules. Simple vacuum or heat drying do not result in a sufficiently low chlorinated solvent content so as to meet FDA regulations, thus creating an essential necessity for a method for encapsulating vitamins, food supplements, oils or pharmaceuticals by the solvent removal technique.
U.S. Pat. No. 6,599,62 discloses a solvent exchange method in order to obtain single-wall microcapsules of pharmaceuticals. The described method is based on an exchange of water and a non-chlorinated organic solvent such as acetic acid, ethyl acetate, methyl acetate, or ethyl formate to form a biodegradable poly(lactic acid-co-glycolic acid) (PLGA) shell around an aqueous drug core. All these solvents meet the FDA regulations.
Few patents disclose techniques for obtaining multi-wall microspheres and microcapsules by various coating processes, which do not apply the solvent removal method, or apply spray-drying technique in the case of volatile organic solvents. U.S. Pat. No. 3,429,827 describes coating of the inner microcapsules with a second polymer shell by spray-drying or interfacial condensation methods. U.S. Pat. No. 4,861,627 describes a single-step method for preparation of multi-wall microspheres from a mixture of any two or three polymers selected from polyanhydrides, polyorthoesters, poly(lactic acid), polystyrene, polyamides, polybutadiene, polyurethanes, and copolymers, which are not soluble in each other but are soluble in a volatile organic solvent. The mixture is suspended in an aqueous solution followed by slow spray-drying of volatile solvent, creating microspheres with an inner core formed by one polymer and an outer layer formed by a second polymer. U.S. Pat. Nos. 5,985,354, 6,511,749 and 6,528,035 disclose preparation of multi-wall polymer microspheres by a similar technique, from hydrophilic, water-soluble polymers that are not soluble in each other at a particular concentration and temperature but have a positive spreading coefficient in solution. U.S. Pat. No. 5,795,570 describes the formation of a second semi-permeable membrane, which is made of polysaccharide gum such as an alkali metal alginate, comprising core microcapsules. More specifically, U.S. patent Publication No. 2003/0222378 discloses microencapsulation of a series of paraffin compounds with an interfacial polymerization process to form double-shell microcapsules with relatively low shell permeability. The inner shell was formed by a reaction between poly(propylene glycol) and bifunctional polyisocyanates, and the outer shell by a reaction between bifunctional polyisocyanates and polyamines that were added to the continuous aqueous phase.
In summary, none of the methods known in the art meets the growing market requirements for a considerable protection factor of the encapsulated substance against oxidation and/or degradation and for the ability to control the release of the encapsulated substance. Hence, there is still a need for an advanced method for stable encapsulation of active substances that simultaneously affords control of its release from the microcapsules.